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Cerium oxide (CeO2) nanoparticles appear to exhibit antioxidant properties which have led some to suggest that these particles may be used to treat medical conditions that are associated with increases in oxidative stress. Conversely, other in vitro and in vivo work has suggested that exposure to CeO2 nanoparticles can, at least under certain conditions, lead to increases in oxidative stress. Herein we attempt to explore the underlying mechanism of this finding. To this end, 7-week old male Sprague Dawley rats (n=72) were randomized to one of two groups: CeO2 nanoparticle (20 nm diameter) instillation (7 mg/kg in 300 microl normal saline) or age-matched saline control (300 microl normal saline). After instillation, animals were sacrificed at 1, 3, 14, 28, 56 and 90 days (n=6/group). Compared to saline-control animals, the concentration of malondialdehyde (MDA) per gram of liver tissue in CeO2 exposed animals was 25%, 31% and 20% higher at days 1, 3, and 90 post exposure (p<0.05) but unchanged at days 14, 28 days and 56. The increases in lipid peroxidation at day 1 and 3 were associated with 32% and 10% increases in the Bax to Bcl-2 ratio (P<0.05) while the ratio of Bax to Bcl-2 was 55%, 62%, and 47% lower at days 14, 28 and 56 (P<0.05). Compared to saline-control, the levels of cleaved caspase-3 (17 kDa and 19 kDa fragments) were by 32% higher and 49% higher (P< 0.05) at days 1 and 3 before being decreased by 35%, 25%, 20%, and 7% at days 14, 28, 56, and 90 respectively (P<0.05). Taken together, these data are suggest that the initial response of the liver to intratracheal instillation of CeO2 nanoparticles is characterized by increased oxidative stress and caspase-3 activation at days 1 and 3 post exposure. Whether these events are associated with hepatic apoptosis and subsequent tissue remodeling is currently under investigation.